3beta-oxy-delta16-allopregnenedione-11, 20 and process



35-OXY-A -ALLOPREGNENEDIONE4L20 AND PROCESS Ralph F. Hirschmann, Westfield, Norman L. Wendler,

Summit, and William V. Ruyle, Westfield, N. J., as-

signers to Merck & (10., Inc., Rahway, N. 3., a corporation of New Jersey No Drawing. Application July 1, 1954, Serial No. 440,845

11 Claims. (Cl. 260-39745) This invention relates to novel compounds of the cyclopentanopolyhydrophenanthrene series and methods of preparing the same. More particularly, it relates to an improved process for the conversion of 20-ketopregnane compounds having a 16-acyloxy substituent to the corresponding A -20-ketopregnene compounds, and to the application of this improved method for the preparation of the new compound, 3(/3)-hydroxy-A -allopregnenedionestituent. This degradation process may be represented.

by partial formulas as follows:

Sapogenin Pseudo-sapogenin (EH; C=O

It is an object of the present invention to provide an improved process for hydrolyzing the oxidation products of pseudo-sapogenins, namely, the 20-ketopregnane compounds, represented by (I) above, having a 16-(6-acy1- oxyisocaprooxy) substituent, to the corresponding A -20- ketopregnene in enhanced yields. It is a further object to provide a process for preparing the novel compound, 3(p3)-hydroxy-A -allopregnenedione-11,20 and acyl derivatives thereof from the corresponding 3-hydroxy-l1- ketosapogenin. Other objects will be apparent from the detailed description hereinafter provided.

In accordance with one embodiment of our invention, We have found that l6-(fi-acyloxyisocaprooxy)-pregnane compounds are converted to the corresponding A -pregnene compound in improved yields by reaction with an alkali metal hydroxide in the presence of non-reactive 2,779,774 Patented Jan. 29, 1957 ice inert solvent. Previously such 16-(6-acyloxyisocaprooxyj-pregnane compounds had been hydrolyzed by reaction with an alcoholic solution of an alkali such as methanolic or ethanolic potassium hydroxide. However, the yields of the desired A -pregnene compound obtained by this process were low, since the alcoholic solvent caused etherification and the production of considerable amounts of the 16-alkoxy compound having the partial formula 0 Alkyl By carrying out this hydrolysis in accordance with our improved process, the formation of this undesirable side product is avoided and the A -20-hetopregnene compounds are recovered in enhanced yields.

In carrying out our improved process the 16-(6-acyloxyisocaprooxy) compound is heated with an aqueous solution of an alkali metal hydroxide and a suitable nonreactive inert organic solvent. In general, the solvents suitableifor our process include those in which the 16- (S-acyloxyisocaprooxy) compounds are soluble or partial- 1y soluble and which will not result in the formation of a 16-alkoxy compound. Solvents particularly suitable for this purpose that might be mentioned are tetrahydrofur-an and dioxane.

Thus, in accordance with our invention sapogenin derivatives such as 3(,6)-acetoxy-16(5-acetoxyisocaprooxy)- allopregnanedione-11,20 and 3(,8)-acetoxy-16-(6-acetoxyisocaprooxy)-a1lopregnanedione-12,2O are reacted by heating With an aqueous solution of an alkali metal hydroxide such as sodium hydroxide, and tetrahydrofuran to form the corresponding A -20ketopregnene compound in enhanced yields. After the reaction is completed, the

desired product can be readily obtained by concentratingthese acyloxy substituents may also be partially hydro lyzed under the reaction conditions. Therefor, we find that it is sometimes desirable to acylate the crude hydrolysis product in order to convert any free hydroxy substituents to the corresponding acyl derivatives. General- 1y however the conditions are sufficiently mild that substantially no hydrolysis of a 3-acetoxy group will occur.

In accordance with a further embodiment of our in- Vention We have found that the novel compound, 3(5)- acetoxy-A -allopregnenedione-11,20, can be readily obtained in high yields from il-ketotigogenin acetate by the 3 acetoxyisocaprooxy)-allopregnanedione-11,20, and reacting this product with aqueous sodiumhydroxide and'tetrahydrofuran. The 3(18)acetoxy-A -allopregnenedione- 11,20 so obtained can be hydrolyzed to form the 3(5)- hydroxy compound which may be acylated in accordance with conventional practice to prepare other acyl derivatives of 3(,6)-hydroxy-A -allopregnenedione-11,20.

This product audits acyl derivative are useful as intermediate products for the preparation of other steroid compounds such as cortisoneand the like. Similarly, the other A -20-ketopregnene compounds prepared in accord ance with our process are useful as intermediateproducts for the preparation of other steroidal compounds.

Thus, the novel products of this invention can'be converted tocortisone in accordance with methods known. in the art. For example, 3 (13)-hydroxy-A -allopregnenedione-11,20 can be catalytically hydrogenated in the presence of palladium catalyst toform the corresponding saturated compound, 3(B)-hydroxy-allopregnanedione-11,20. The latter compound can be converted by reaction with hydrogen cyanide to the corresponding 20-cyano-hydrin which on dehydration with phosphorous oxychloride yields the corresponding AH'ZO-ZO-CYQHO derivative. On treating thisproduct with osmium'tetroxide and hydrolyzing the resulting osmate ester 3( ,8),l7-dihydroxy allopregnane- (hone-11,20 is obtained. This compound can then be oxidized by treatment with chromium trioxide inthepresence of acid to form the corresponding S-keto compound.

The 3,1l,20-tril :eto-l7(u)-hydro:iy allopregnane so prepared is then converted to the corresponding 21-acetoxy derivative by reaction with lead tetra-acetate in acetic acid in accordance with methods known in the art. The'resulting 3 .lt,20-trikcto 17(a) hydroxy-ZI-acetoxy allopregname is then converted to cortisone acetate utilizing procedure described in the art, comprising brominating the allopregnane compound to obtain the corresponding 2,4-dibromo derivative treating the dibromide with sodium iodide to form the A -2-iodo-3-keto compound, and reacting the latter product withchromous chloride to obtain cortisone acetate.

The following examples are presented as specific illustrative embodiments of our invention.

EXAMPLE 1 A mixture of 1.50 g. of ll-ketotigogenin acetate (prepared as described in copending application Serial No. 215,026, filed March 10, 1951) and five milliliters of acetic anhydride was heated in a sealed tube at 200 C. for ten hours. Removal of excess acetic anhydride in vacuo left an oily residue. Chromatography of this oily residue on acid washed alumina gave amen-crystalline fraction weighing 1.31 g. This was dissolved in 10 ml. of ethylene dichloride and to the stirred solution was added 0.70 g. of chromium trioxide dissolved in 15 ml. of 90% acetic acid. The mixture was stirred two hours at room temperature, one ml. of ethanol wasadded, and the mixture was concentrated in vacuo to a volume of ten milliliters. T he mixture was diluted with ml. of water, and extracted with ether. The etherlayer was washed with water, andthen with aqueous sodium bicarbonate. T heiether. solution vwas dried over sodium sulfate and the solvent removed by distillation.

The resulting residue, 3"(;B)-acetoxy-16-(6-acetoxy isocaprooxy)-allopregnauedione-11,20 was refluxed for 30 minutes with a mixture of 15 ml. of 2.5 N sodium hydroxide solution and 15ml. of tetrahydrofuran. Themixture was concentrated in vacuo to about one-half volume, and was extracted with ether. The dried ether solution was concentrated to-drynessiand'the residue was recrystallized frommethanol. Yield, 0.40 g., MJP. 1825-185 C. ,The product washeated on the steam bath in a mixture .of 3 ml. pyridine and 0.5 ml. acetic anhydride. The product, isolated .by.conventionalvmethods, was found to melt at 1.83% .C. Recrystallizedfrom methanol in rectangular prisins,.M. P. 183.5-1 85 C. Absorption spectrum xmax. 2345 A.;

E1? v243 (inethanol) [a'] +64.5 ;(c.=1.24 in CHCla).

Airalysis.-Calcd. for C23H32O4: 'C, 74.16; H, 8.66. FoundzC, 73.93; H,8.83.

The 3 (/3)-acetoxy-A -allopregnenedione-11,20 was hydrolyzed to obtain 3(t8) hydroxy-A -allopregnenedione- 11,20 having a melting point of 220-221.5 ,C.

In accordance with conventional methods, this'latter compound can be acylated to obtain other 3-acyloxy derivatives.

Conversion of 11 -ketotigo genin acetate to 3( 8)-acetoxy- A -all0pregnenedi0ne-1 1,20

NaOH

tetrahydrofuran A00 EXAMPLE 2 Conversion of pseudohecogenin diacetate to 3(5)-acet- 0xy-A -all0pregnenMimic-12,20

A solution of 4.5 g. of pseudohecogenin diacetate (I) was dissolved in a mixture of 175 cc. of glacial acetic acid, cc. of water and six drops of methanol was ozonized at 0 C. The resulting reaction mixture was allowed to stand at room temperature, and then was concentrated to a small volume under diminished pressure. The ozonide was decomposed by treatment with zinc and acetic acid and the ozonized product (II) was recovered by concentrating the reaction mixture under diminished pressure, dissolving the residue in ether, filtering to remove the zinc salts, washing the ether to remove acidic substances, and evaporating the ether. The residue so obtained weighed 4.41 g.

The residue so obtained was dissolved in 40 cc. of tetrahydrofuran, 36 cc. of 2.5 N sodium hydroxide added thereto, and the resulting mixture was heated on a steam bath for 30 minutes in a nitrogen atmosphere. The reaction mixture was then concentrated under diminished pressure to obtain an oily residue which was dissolved in ether and washed free of base. The dried ethereal solution afforded 2.5 g. of a crystalline product which was reacetylated by reaction with acetic anhydride in the presence of pyridine to yield about 2.5 g. of crude 3(5)- acetoxy A allopregnenedione 12,20, A max. 227 (E% 139). (The pure compound shows an E% of about AGO ' 202 at 227-228 mu.)

The crude product so obtained was dissolved in ether and sufficient Skelly Solve C (a petroleum hydrocarbon fraction) added to incipient precipitation. The resulting solution deposited 1.25 g. of a crystalline substance which was dissolved in 40 cc. of benzene. The benzene solution was chromatographed over 60 g. of acid washed alumina which was washed with more benzene, and finally eluted with a l to 1 chloroform-benzene mixture. The 3(5) acetoxy A allopregnencdione 12,20 was recovered from the resulting eluates in the form of crystals melting at ISO-182 C.

The ether-Skelly Solve C mother liquors were concentrated under diminished pressure to obtain 1.14 g. of residue which was chromatographed over acid washed alumina by the method described above to yield additional amounts of the desired product. The total yield of 3(5) acetoxy A allopregnenedione 12,20 was about 50% of theory.

In a further experiment, 0.210 g. of the crude ozonide was hydrolyzed by the above described procedure and the 3(5) acetoxy A pregnenedione 12,20 (III) (0.52 g. melting at 172179 C.) was isolated without recourse to reacetylation. The melting point of the product so obtained was not depressed on admixture with an authentic sample of the product melting at 181-183" C. This indicates that the reacetylation step is unnecessary and that the hydrolysis procedure does not result in the removal of the acetyl group.

Various changes and modifications may be made in carrying out the present invention without departing from the spirit and scope thereof. Insofar as these changes and modifications are within the purview of the annexed claims, they are to be considered as part of our invention.

We claim:

1. The process for preparing 3(5) acyloxy A allopregnenedione-l1,20 which comprises reacting 3(5)- acyloxy 16 (6 acyloxyisocaprooxy) allopregnane- (Hone-11,20 with an aqueous solution of an alkali metal hydroxide in the presence of a non-reactive inert organic solvent substantially free from lower aliphatic alcohols.

2. The process for preparing 3(5)-acyloxy-A -allopregnenedione-l2,20 which comprises reacting 3(5)- acyloxy 16 (6 acyloxyisocaprooxy) allopregnanedime-12,20 with an aqueous solution of an alkali metal hydroxide in the presence of a non-reactive inert organic solvent substantially free from lower aliphatic alcohols.

3. The process for preparing 3(5) acetoxy A" allopregnenedione-11,20 which comprises reacting 3(5) acetoxy 16 (6 acetoxyisocaprooxy) allopregnanedione-11,20 with an aqueous solution of an alkali metal hydroxide in the presence of tetrahydrofuran.

4. The process for preparing 3(5) acetoxy A allopregnenedione-12,20 which comprises reacting 3(5) acetoxy 16 (6 acetoxyisocaprooxy) allopregnanedione-12,20, with an aqueous solution of an alkali metal hydroxide in the presence of tetrahydrcfuran.

5. The process for preparing 3(5) acetoxy A alopregnenedione-l1,20 which comprises reacting 3(5) acetoxy 16 (6 acetoxyisocaprooxy) allopregnanedione-11,20 with an aqueous solution of sodium hydroxide in the presence of tetrahydrofuran.

6. The process for preparing 3(5) acetoxy A allopregnenedione-l2,20 which comprises reacting 3(5) acetoxy 16 (6 acetoxyisocaprooxy) allopregnanedime-12,20 with an aqueous solution of sodium hydroxide in the presence of tetrahydrofuran.

7. The process for preparing 3(5) acetoxy A allopregnenedione-11,20, which comprises heating ll-ketotigogenin acetate with acetic anhydride, oxidizing the resulting reaction product With chromic oxide, and reacting the oxidized product with an aqueous solution of an alkali metal hydroxide in the presence of a non-reactive inert organic solvent substantially free from lower aliphatic alcohols.

8. The process for preparing 3(5) acetoxy A allopregnenedione-11,20 which comprises heating ll-ketotigogenin acetate with acetic anhydride at about 200 C., oxidizing the resulting reaction product with chromic oxide at room temperature, and reacting the oxidized product with an aqueous: solution of sodium hydroxide in References Cited in the file of this patent Chamberlain: I. Am. Chem. Soc. 73, 2396-97 (1951). 

1. THE PROCESS FOR PREPARING 3(B) - ACYLOXY -$16 ALLOPREGNENEDIONE-11,20 WHICH COMPRISES REACTING 3(B) ACYLOXY - 16 - (8 - ACYLXYISOCAPROOXY) - ALLOPREGNANEDIONE-11,20 WITH AN AQUEOS SOLUTION OF AN ALKALI METAL HYDROXIDE IN THE PESENCE OF A NON-REACTIVE INERT ORGANIC SOLVENT SUBSTANTIALLY FRE FROM LOWER ALIPHATIC ALCOHOLS. 